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1.  Dynamic Indices of Methamphetamine Dependence and HIV Infection Predict Fluctuations in Affective Distress: A Five-year Longitudinal Analysis 
Journal of affective disorders  2013;151(2):10.1016/j.jad.2013.07.036.
Methamphetamine (METH) use and human immunodeficiency virus (HIV) infection are highly comorbid, and both are associated with increased prevalence of affective distress. Delineating the trajectory of affective distress in the context of METH dependence and HIV infection is important given the implications for everyday functional impairment, adverse health behaviors, and increased risk for adverse health outcomes.
We conducted a five-year longitudinal investigation involving 133 METH-dependent (74 HIV seropositive) and 163 non-METH-dependent (90 HIV seropositive) persons to examine both long-standing patterns and transient changes in affective distress. Mixed-effect regression models with random subject-specific slopes and intercepts evaluated the effect of METH dependence, HIV serostatus, and related variables on affective distress, as measured by the Profile of Mood States.
Transient changes in affective distress were found to be greater among those with a diagnosis of current MDD, briefer durations of abstinence from METH, and higher quantity of METH consumed. Weak associations were observed among static (time-independent predictors) covariates and long-standing patterns in affective distress.
Study lacked data pertaining to the participants’ involvement in METH treatment and relied on respondent-driven sampling.
Our longitudinal investigation of the trajectory of affective distress indicated that specific and dynamic indices of current METH use were associated with greater transient changes in mood. In the evaluation and treatment of affective distress, recency and quantity of current METH use are important to consider given their association with heightened affective distress and mood instability over time.
PMCID: PMC3845675  PMID: 24012068
Affective distress; Methamphetamine; Dependence; HIV; Longitudinal
2.  Etravirine in CSF is highly protein bound 
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
3.  Normative data and validation of a regression based summary score for assessing meaningful neuropsychological change 
Reliable detection and quantification of longitudinal cognitive change are of considerable importance in many neurological disorders, particularly to monitor central nervous system effects of disease progression and treatment. In the current study, we developed normative data for repeated neuropsychological (NP) assessments (6 testings) using a modified Standard Regression-Based (SRB) approach in a sample that includes both HIV-uninfected (HIV−, N=172) and neuromedically stable HIV-infected (HIV+, N=124) individuals. Prior analyzes indicated no differences in NP change between the infected and uninfected participants. The norms for change included correction for factors found to significantly affect follow-up performance, using hierarchical regression. The most robust and consistent predictors of follow-up performance were the prior performance on the same test (which contributed in all models) and a measure of prior overall NP competence (predictor in 97% of all models). Demographic variables were predictors in 10%-46% of all models and in small amounts; while test retest interval contributed in only 6% of all models. Based on the regression equations, standardized change scores (z-scores) were computed for each test measure at each interval; these z scores were then averaged to create a total battery change score. An independent sample of HIV− participants who had completed 8 of the 15 tests was used to validate an abridged summary change score. The normative data are available in an electronic format by email request to the first author. Correction for practice effects based on normative data improved the consistency of NP impairment classification in a clinically stable longitudinal cohort after baseline.
PMCID: PMC3151558  PMID: 21391011
Normative data; longitudinal studies; regression; regression change score; SRB; practice effect
4.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
5.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
6.  Incidence and Nature of Cognitive Decline Over One Year Among HIV-infected Former Plasma Donors in China 
AIDS (London, England)  2010;24(7):983-990.
To quantify and characterize the nature of cognitive change over one year in a cohort of HIV+ former plasma donors in rural China.
Observational cohort study
192 HIV+ and 101 demographically comparable HIV− individuals, all former plasma donors, who lived in a rural part of China, received comprehensive medical and neuropsychological (NP) examinations. At study entry 56% of HIV+ group was on combination antiretroviral treatment (cART) and 60.9% at followup. Multiple regression change score approach was used with the HIV− sample to develop norms for change that would be then applied to the HIV+ participants. Followup test scores adjusted for the control group practice effect.
53 HIV+ individuals (27%) developed significant cognitive decline as compared to five (5%) of HIV− individuals. Cognitive decline was predicted at baseline by AIDS status, lower nadir CD4, and worse processing speed; at follow-up, it was associated with lower current CD4 and failure of viral suppression on cART. NP decline also was associated with decreased independence in activities of daily living. Using NP-impairment scores that were corrected for “practice” on repeated testing, we found that among the decliners, 41.5% (N=22) had incident impairment, while 38% (N=20) declined within the impaired range and another 20.7% (N=11) declined within the normal range.
This study demonstrates that despite ongoing cART, cognitive decline in HIV+ people is common over a one year follow-up. Regression-based norms for change on Western NP tests can be used to detect disease-related cognitive decline in a developing country.
PMCID: PMC2898923  PMID: 20299964
HIV/AIDS; Neurocognitive Disorders; Incidence Studies; China; Longitudinal Studies; Neuropsychological Tests; Antiretroviral Therapy; Highly Active
7.  HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors 
Journal of Neurovirology  2010;17(1):3-16.
Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
PMCID: PMC3032197  PMID: 21174240
HIV; Combination antiretroviral therapy; HIV dementia
8.  Estimating the Accuracy of Anal Cytology in the Presence of an Imperfect Reference Standard 
PLoS ONE  2010;5(8):e12284.
The study aim is to estimate sensitivity and specificity of anal cytology for histologic HSIL in analyses adjusted for the imperfect biopsy reference standard.
Methods and Principal Findings
Retrospective cohort study of an anal dysplasia screening program for HIV infected adults. We estimated the prevalence of histologic HSIL by concurrent cytology category and the associated cytology ROC area. Cytology operating characteristics for HSIL were estimated and adjusted for the imperfect reference standard by 3 methodologies. The study cohort included 261 patients with 3 available measures: (1) referral cytology; (2) HRA cytology; and (3) HRA directed biopsy. The prevalence of biopsy HSIL varied according to the concurrent HRA cytology result: 64.5% for HSIL or ASC-H, 12.6% for LSIL, 10.9% for ASCUS, and 6.3% for no abnormality. The cytology ROC area was 0.78. The observed prevalence of HSIL was 37% (referral cytology), 24% (HRA cytology), and 24% (HRA biopsy). Unadjusted estimates of sensitivity and specificity of cytology were 0.66 and 0.90, respectively. Adjusted estimates varied from 0.47–0.89 (sensitivity) and 0.89—1.0 (specificity).
Analysis of a single dataset yields widely different estimates of anal cytology operating characteristics that depend on difficult to verify assumptions regarding the accuracy of the imperfect reference standard.
PMCID: PMC2924391  PMID: 20808869
9.  Two-Year Prospective Study of Major Depressive Disorder in HIV-Infected Men 
Journal of affective disorders  2007;108(3):225-234.
The risks and factors contributing to major depressive episodes in HIV infection remain unclear. This 2-year prospective study compared cumulative rates and predictors of a major depressive episode in HIV-infected (HIV+) men (N=297) and uninfected (HIV−) risk-group controls (N=90).
By design participants at entry were without current major depression, substance dependence or major anxiety disorder. Standardized neuromedical, neuropsychological, neuroimaging, life events, and psychiatric assessments (Structured Clinical Interview for DSM III-R) were conducted semi-annually for those with AIDS, and annually for all others.
Lifetime prevalence of major depression or other psychiatric disorder did not differ at baseline between HIV+ men and controls. On 2-year follow up those with symptomatic HIV disease were significantly more likely to experience a major depressive episode than were asymptomatic HIV+ individuals and HIV− controls (p<0.05). Episodes were as likely to be first onset as recurrent depression. After baseline disease stage and medical variables associated with HIV infection were controlled, a lifetime history of major depression, or of lifetime psychiatric co-morbidity (two or more psychiatric disorders), predicted subsequent major depressive episode (p <0.05). Neither HIV disease progression during follow-up, nor the baseline presence of neurocognitive impairment, clinical brain imaging abnormality, or marked life adversity predicted a later major depressive episode.
Research cohort of men examined before era of widespread use of advanced anti-HIV therapies.
Symptomatic HIV disease, but not HIV infection itself, increases intermediate-term risk of major depression. Prior psychiatric history most strongly predicted future vulnerability.
PMCID: PMC2494949  PMID: 18045694
10.  The Hound of the Baskervilles effect: natural experiment on the influence of psychological stress on timing of death 
BMJ : British Medical Journal  2001;323(7327):1443-1446.
To determine whether cardiac mortality is abnormally high on days considered unlucky: Chinese and Japanese people consider the number 4 unlucky, white Americans do not.
Examination of cardiac and non-cardiac mortality on and around the fourth of each month in Chinese and Japanese subjects and white controls.
United States.
All Chinese and Japanese (n=209 908) and white (n=47 328 762) Americans whose computerised death certificates were recorded between the beginning of January 1973 and the end of December 1998.
Main outcome measures
Ratio of observed to expected numbers of deaths on the fourth day of the month (expected number was estimated from mortality on other days of the month).
Cardiac mortality in Chinese and Japanese people peaked on the fourth of the month. The peak was particularly large for deaths from chronic heart disease (ratio of observed to expected deaths = 1.13, 95% confidence interval 1.06 to 1.21) and still larger for deaths from chronic heart disease in California (1.27, 1.15 to 1.39). Within this group, inpatients showed a particularly large peak on the fourth day(1.45, 1.19 to 1.81). The peak was not followed by a compensatory drop in number of deaths. White controls, matched on age, sex, marital status, hospital status, location, and cause of death, showed no similar peak in cardiac mortality.
Our findings of excess cardiac mortality on “unlucky” days are consistent with the hypothesis that cardiac mortality increases on psychologically stressful occasions. The results are inconsistent with nine other possible explanations for the findings—for example, the fourth day peak does not seem to occur because of changes in the patient's diet, alcohol intake, exercise, or drug regimens.
What is already known on this topicLaboratory studies show that cardiovascular changes occur after mild psychological stress, but it is unclear whether fatal heart attacks increase after psychological stressPrevious non-laboratory studies were unable to control for physical and medical changes associated with most stressful occasionsWhat this study addsUnlike white people, Chinese and Japanese associate the number 4 with death.Cardiac mortality in Chinese and Japanese Americans peaks on the fourth day of the month, even though this date is not consistently associated with changes in the physical or medical environmentIn The Hound of the Baskervilles, Charles Baskerville died from a heart attack induced by stress; this “Baskerville effect” seems to exist in fact as well as in fiction
PMCID: PMC61045  PMID: 11751347

Results 1-10 (10)